2.4 Primary outcome: reduction in anhedonia scores at 8 weeks (from 4 to 12 weeks)
2.4.1 Pairwise meta-analysis
Figure 2. Forest plot for symptoms of anhedonia (primary outcome) comparing pro-dopaminergic interventions vs placebo for individuals with anhedonia at 4-12 weeks (primary timepoint). SMD: standardised mean difference, 95%CI: 95% confidence intervals, SD: standard deviation.
6 studies contributed with data to the meta-analysis with a total of 2076 participants (1140 allocated to pro-dopaminergic interventions, 936 allocated to pill placebo).
The comparative effect of pro-dopaminergic interventions versus placebo showed an effect favouring pro-dopaminergic interventions with a SMD of -0.244 (95%CI from -0.456 to -0.031). There is some heterogeneity as shown by the 95% prediction interval from -0.74 to 0.252.
2.4.2 Risk of bias
Figure 3. Risk of bias assessment.
Evidence for the efficacy of pro-dopaminergic interventions vs placebo in improving anhedonia was rated moderate for risk of bias. 50% of the included studies had an overall high risk of bias while the other 50% had moderate risk of bias, primarily due to missing outcome data, issues with outcome measurement, and selective reporting of findings. The extent to which the result was affected by across-study biases is unclear and all included studies were rated at least moderate in domain 5, selection of results. This result was judged to be at moderate risk of bias due to indirectness as while there was no clear indication of indirectness in terms of population, comparator, or outcomes, 80% of the studies measured the same intervention, bupropion.
2.4.3 Reporting bias
We evaluated the reporting bias using the ROB-ME tool (Page et al. 2023), taking into account the usable data from the eligible studies identified in the search, the comprehensiveness of the search, small-study effects, and potential patterns of missingness. We followed the algorithm to assign a low or high risk of reporting bias, or to express some concerns, by answering signalling questions related to the domains mentioned above.
2.4.4 Meta-regression analyses
We did not perform any meta-regressions (mean anhedonia baseline score, mean anxiety baseline score, age, sex, planned treatment duration) as the total number of studies was below 10.
2.4.5 Sensitivity analyses
We performed a series of random effects network meta-analyses on the MADRS “inability to feel” item (aggregated IPD from 34 studies, 14054 participants). First, we included all the available studies and compared all the antidepressants against placebo.
2.4.5.1 Aggregated IPD, all antidepressants and placebo, random effects network meta-analysis
Figure 4. Comparative effect sizes of antidepressants versus placebo.
The comparative effect of bupropion versus placebo was -0.12 (SMD, 95%CI from -0.25 to 0.00; 34 studies, 14054 participants), lower than what we could observe from the retrieved data (random effects pairwise meta-analysis, bupropion versus placebo): -0.22 (SMD, 95%CI from -0.44 to 0.01; 5 studies, 2020 participants).
Figure 5. Forest plot for symptoms of anhedonia (primary outcome) comparing bupropion versus placebo for individuals with anhedonia at 4-12 weeks (primary timepoint). SMD: standardised mean difference, 95%CI: 95% confidence intervals, SD: standard deviation.
2.4.5.2 Aggregated IPD, bupropion versus placebo, random effects pairwise meta-analysis
We also performed a random effects pairwise meta-analysis of bupropion versus placebo based on the aggregated IPD, resulting in estimates comparable to the network meta-analytical model (SMD -0.12, 95%CI from -0.29 to 0.05; 4 studies, 1085 participants).
2.4.5.3 Aggregated IPD and early studies identified in this living systematic review, random effects pairwise meta-analysis
Finally, we performed a random effects pairwise meta-analysis including aggregate data from both sources (IPD and retrieved as aggregated). As three studies (Hewett 2009 - 87997883, Hewett 2010a - 87997755, Koshino 2013 - 87997374) were available in both sources, we prioritised aggregate IPD over data retrieved as aggregated. The comparative effect of bupropion versus placebo was -0.19 (SMD, 95%CI from -0.33 to 0.04; 6 studies, 2489 participants)
